O,n-diphenylthiocarbamic acid esters

ABSTRACT

CERTAIN O,N-DIPHENYL-CARBAMIC ACID ESTERS IN WHICH ONE PHENYL MOIETY IS SUBSTITUTED IN THE 2-POSITION BY A HALOGENATED PHENOXY RADICAL ARE DISCLOSED AS MICROBICIDALLY ACTIVE COMPOUNDS. A METHOD FOR CONTROLLING MICROORGANISMS WITH THE AID OF SUCH COMPOUNDS AND COMPOSITIONS CONTAINING THEM ARE ALSO DESCRIBED.

United States Patent 3,790,615 0,N-DIPHENYLTHIOCARBAMIC ACID ESTERS Walter Traber, Riehen, Heinz Hamhtick, Binningen, and Anton Georg Weiss, Benken, Switzerland, assignors to Ciba-Geigy Corporation, Ardsley, N.Y.

No Drawing. Original application Jan. 26, 1970, Ser. No.

5,954, now Patent No. 3,721,699. Divided and this application Jan. 2, 1973, Ser. No. 320,390

Int. Cl. C07c 125/06 U.S. Cl. 260-455 A Claims ABSTRACT OF THE DISCLOSURE Certain O,N-diphenyl-carbamic acid esters in which one phenyl moiety is substituted in the 2-position by a halogenated phenoxy radical are disclosed as microbicidally active compounds. A method for controlling microorganisms with the aid of such compounds and compositions containing them are also described.

This is a division of application Ser. No. 5,954, filed on Jan. 26, 1970, now US. Pat. 3,721,699.

The present invention concerns new O,N-diphenyl-carbamic acid esters, process for the production of these compounds as well as compositions and methods for the control of microorganisms employeding the new carbamic acid esters.

The new O,N-diphenyl-carbamic acid esters (carbanilic acid-phenyl esters) correspond to the Formula I R: R4 R5 in this formula:

R represents a phenoxy radical substituted by at least one and at most three identical or diifering halogen atoms,

of the symbols R R and R at least one represents chlorine or bromine, the others each independently represent hydrogen, chlorine or bromine,

R and R each independently represent hydrogen, halogen, lower alkyl, lower alkoxy, lower halogenalkyl, nitro or hydroxy,

R represents hydrogen, halogen, lower alkyl, lower alkoxy, dialkylamino, hydroxy, and

X represents oxygen or sulfur.

In Formula I, R is in particular one of the following halogenated phenoxy radicals: 4-chlorophenoxy, 4-bromophenoxy, 2,4-dichlorophenoxy, 2,4-dibromophenoxy, 2,4,5-trichlorophenoxy.

Lower alkyl and lower alkoxy radicals R to R have from 1 to 4 carbon atoms. As halogenalkyl, trifluoromethyl is preferred. The alkyl substituents in a dialkylamino group are radicals having 1 to 4 carbon atoms in particular the methyl radical. By halogen represented by R R and/or R is meant fluorine, chlorine, bromine and iodine, especially however, fluorine, chlorine and/or bromine.

3,790,615 Patented Feb. 5, 1974 ice The new O,N-diphenyl-carbamic acid esters are obtained according to the invention, either (a) by converting a phenol of the Formula 11 as such or in the form of one of its alkali metal or alkaline earth metal salts, with phosgene or thiophosgene into an acid chloride of the Formula III X E; (III) and reacting this with an aniline of the Formula IV s Rz-Q-NH: 1

Rs mQaro o In the Formulas I to V, the symbols R to R and X have the meanings given for Formula I.

The process according to the invention is preferably carried out in the presence of a solvent or diluting agent and of an acid-binding agent (proton acceptor).

Examples of suitable solvents or diluting agents are: hydrocarbons, such as toluene, benzene or ligroin, halogenated hydrocarbons, such as chloroform, carbon tetrachloride or chlorobenzene, amides such as dimethylformamide, ethers and ether-like compounds such as tetrahydrofuran, dioxan or diisopropylether, ketones such as acetone or methyl-ethylketone. Acid-binding agents are preferably organic bases, e.g. tertiary amines such as pyridine, triethylamine etc., inorganic bases such as the hydroxides and carbonates of alkali metals and alkaline earth metals.

In the following examples, the production of some of the diphenyl-carbamic acid esters of Formula I is described. The temperatures are given in degrees centigrade.

EXAMPLE 1 (a) about g. of phosgene are introduced at 0 into 500 ml. of toluene. To this solution there is added dropwise at 0 to 5, 21 solution of 289.5 g. of 4,2',4'-trichloro- Z-hydroxy-diphenyl ether in 700 ml. of toluene, and 100 g. more of phosgene are introduced. While stirring, a solution of 111.3 g. of triethyl amine in 200 ml. of toluene is then added to the reaction mixture. After standing for several hours at room temperature, the excess phosgene is removed, the triethylamine-hydrochloride is separated,

the solvent is removed by distillation, the residue is fractionated in vacuum. The 2-(2,4'-dich1orophenoxy)-5- chlorophenyl-thiocarhonyl chloride boils at l75184 0.05 torr (n =1.6275).

(b) A solution of 24.2 g. of 3,5-dirnethylaniline in 150 5 and the solvent is removed from the filtrate. The residue ml. of benzene is added dropwise at 5 during 1.5 hours is fractionated, the O-[2-(2',4-d1chlorophenoxy)-5-chloroto a solution of 36 g. of O-[2-(2',4'-dichlorophenoxy)- phenyH-canbonyl chlorlde boils at ISO-184 and 0.5 torr. 5 chlorophenyl]-thio arbonylchloride in 150 ml. of (b) 35.2 g. of -[2-(2, '-d chl rophenoxy)--chloro benzene. The mixture is then stirred for 12 hours at room phenyl]-carhony1 chloride, dissolved in 300 ml. of temperature, shaken out with water, and dried over sodium acetone are treated dropwlse at to W1th a 801111 sulfate. After the solvent has been removed by distillaof 32.4 g. of 3,5-d1chloramlme m 150 ml. of acetone. tion, the residue of the O-[2-(2',4'-dichlorophenoxy)-5- The reaction mixture is then allowed to stand for 3 chlorophenyl]-thiocarbamic a id-N-(3,5-dimethylphenyl)- hours at T0011! temperature, P 011m Water, d the ester, recrystallized from benzene/petroleum ether, has precipitate which separates out after several hours is re- 15 a melting point of 102-104". moved by filtration. After recrystallizing several times EXAMPLE 3 from cyclohexaue and benzene/ petroleum ether, N-(3,5 dichlorophenyl)-carbamic acid-0 [2 (2,4'-dichloro- A solution of 19.8 g. of 3-br0mo-phenyl-1socyanate 1n phenoxy)-5-chlorophenyl]-ester having a melting point 50 ml. of ligroin is added dropwise to a suspension of 30 of132-134" isobtained. 20 g. of 4'-bromo-4-chloro-Z-hydroxy-diphenyl ether in 100 EXAMPLE 2 ml. of ligroin. After the addition of 2 ml. of triethylamine, the mixture is refluxed for 1 hour and then cooled. The A 8011111011 Of 150 0f thlophosgene In 400 1111- Of precipitate which separates is separated, and recrystallized chloroform is added to a solution of 289.5 g. of 2',4'- from benzene/petroleum ether (1:1). dichloro-2-hydroxy-4-chloro-diphenyl ether in 400 ml. of The N-(3-bromophenyl)-carbamic acid-O-[Z-(4-bromochloroform, and colored to 5. While stirring vigorously, phenoxy)-5-chlorophenyl]-ester has a melting point of an aqueous sodium hydroxide solution, 50 g. of sodium 116. hydroxide dissolved in 790 ml. of water, is then added The following O,N-diphenyl-carbarnic acid esters are dropwise in such a manner that the temperature does not prepared from the correspondingly substituted Z-hydroxyexceed 15. The reaction mixture is then stirred for 2 diphenyl ethers or Z-phenoxyphenyl-carbonyl chlorides in hours at room temperature, the organic phase is separated, accordance with the procedures described in the foregoing Washed with water, and dried over sodium sulfate. After examples.

TABLE 1 Melting point, Number Compound degrees 1 N-(4-fiuorophenyD-carbamie acid-O-[2-(4-chlorophenoxy)-5-chlorophenyll-ester 128-130 2- N -(3-chlorophenyl)-carbamic acid-O-[2-(4-ehlorophenoxy)-5-ch1orophenyl]-ester 112-113 3- N-(3-bromophenyD-carbamic acid-O -[2-(4-chlorophenoxy)-5-chlorophenyll-ester 99-100 4-- N-( l-ehlorophenyl)-thi0earbarnic acid-O-[2-(4'-chlorophenoxy)-5-chlorophenyll-es 100-102 5-. N-(B-brornophenyD-thioearbamic acid-G-[2-(4'-chlorophenoxy)-5-chlorophenyl]-ester 105-107 6.- N- (2,4-dich10rophenyl)-carbamic acid-O-[2-(4'-eh1orophenoxy)-5-chloropheny ll-ester- 116-117 7 N-(3,4-dichlorophenyl)-carbamic acid-O-[2-(4-chlorophenoxy)-5-chlorophenyll-ester 146-147 8 N-(3-trifiuoromethylphenyl)-earbamic acid-0 -[2-(4-chlorophenoxy)-5-chlorophenyl]-ester 82-83 9-. N- (3-trifiuoromethyl-a-chlorophenyl)-carbarnic acid-O -[2-(4-chlorophenoxy)-5-cl110r0pheny ll-es 179-180 10. N-(3-trifluoromethy1-4-ch1orophenyl)-thi0carbamic acid-O -[2-(4-chlorophenoxy)-5-chlor0phenyl]-e 98-100 11--. N- (3-trifluoromethyl-6-chlorophenyD-thiocarbamic acid-O-[2-(4-ch1orophenoxy)-5-ehlor0phenyl]-ester 95-97 12--- N-(4-methy1phenyD-carbamie acid-Q-[Z-(M-chlorophenoxy)-5-chlorophenyl]-ester 102-104 13." N-(4-methylphenyD-thioearbamic aeid-O-l2-(4'-chlorophenoxy)-5-chloropheny1]-ester- 131-133 14--- N-(2-methylphenyD-thiocarbamic acid-O-[2-( 1ch1or0phenoxy) -5-chlorophenyl]-ester 92-96 15-.. N-(3,5-dimethylphenyl)-thiocarhamie acid-O-{Z-(4-eh1orophenoxy)-5-ch10rophenyl]est 101-102 16-.- N-(B-methoxyphenyD-carbamie acid-O-[2-(4'-ehlorophenoxy)-5-ehlorophenyl]ester- 76-77 17.... N-(3-methoxyphenyl)thioearbamie aOid-O-[Z-(4-chlorophen0xy)-5chlorophenyl]-ester 84-86 18.-- N-(4-ehlorophenyD-carbam1e acid-O -[2-('1-bron1ophenoxy)-5-chlorophenyl]-ester 150-151 19-.- N-(S-bromophenyD-carbamic acid-Q-[2-(4-bromophenoxy)-5-ehlorophenyl]-ester 11 20..- N-(3,4-diehl0rophenyl)-carbamic acid-0-[2-(4-bromophenoxy)-5-chlorophenyl]-este 142-143 21-.- N-(B-trifiuoromethylphenyl)carhamic acid-O-[2-(4-bromophenoxy)-5-chlorophenyl]-es 84-86 22--- N-(2-methy1phenyD-carbamic acid-O-[2-(4'-br0mophenoxy)-5-ehl0ropheny l]-ester 98 23 N-(3-ch1orophenyD-earbamic acid-Q -[2-(4-chlorophenoxy)-5-bromopheny ll-ester-.. 116-118 24 N-(2,4-dieh1orophenyl)-carbam1c acid-O-[2-(1'-chlorophenoxy)-5-bromophenyl]-este 122-121 25 N-(3-trlfiuoromethyl-t-ehlorophenyl)carbamic acid-O -[2-( 1-ch10r0phenoxy)-5-bromopheny 136-133 26. N-(3,5)-bis-(trifluoromethylphenyl)-carbamic acid-O-[2-( 1-chlorophenoxy)-5-bromopheny l]-ester 129 27- N-(3-methoxyphenyD-carbamic acid-O -[2-(4ch1orophenoxy)-5-bromophenyll-ester 76 28- N-(3,4-diehlorophenyD-carbamie acid-O -[2-( t-br0m0phen0xy)-5-bromophenyl]-ester- 152-154 29 N-(3-trifluoromethylphenyl)-carbamic acid-O-[2-(4-bromophenoxy)-5-bromophenyl]- 88-89 30- N-(3-methylphenyD-carbamic acid-0-[2-(4-bromophenoxy)-5-bromophenyl]-ester 11 1-116 31- N(4-methoxyphenyl)-carbamic aeid-O-[2-(4'-bromophenoxy)-5-bromophenyl]-ester 135-137 32- N-( l-chlorophenyl)-carbarnic acid-O-[2-(4-chlorophenoxy)4-brom0-5-ehlorophenyl]ester. 155-160 33- N-(3-ehloropheny1)-carbamic acid-O-l2-(4-ehlorophenoxy)A-bromo-dehlorophenyl]-ester 120-121 34- N-(3-brornophenyl)-carba.mic acid-O-[2-(4-chlorophenoxy)A-hromo-Erchlorophenyll-ester. 120-121 35- N-(4-bromopheny1)-thiocarbanic acid-O-l2-(4-chlor0phen0xy)4-hr0mo-5-chlorophenyl]-ester 127-128 36- N-(3,4-dichloropheny1)-carbamic acid-O-[Z-(4'ch1orophenox1;)-4-bromo-5-ehl0rophenyl1ester 162-163 37 N-(3-trirluoromethyl--chlorophenyl)-carbanic acid-O-l2-(4-chloro henoxy)4-bromo-5-chlorophenyl]ester- 145-147 38- N-(3-trifiuoromethylphenyl)carbamic acid-O-l2-(4-ch1orophenoxy -4-bromo-5-ch1orophenyl]ester 122-124 39. N-(3-trifluoromethylphenyl)-thioearbanic acid-O-l2-( 1'-chlor0phenoxy)-4-bromo-5-chlorophenyl]-ester 75-77 40 N-(4-methylphenyl)-carbamic acid-O-l2-(1-chl0r0phen0xy)-4-br0m0-5-chlorophenyl]-ester 135-138 41 N-(3-methoxypheny1)-carbamic acid-O-l2-( 1-ehlor0phen0xy) -4-bromo-5-chlorophenyl]-ester 150-151 42-. N -(3,4-d ichlorophenyl)-carbamic acid-O-l2-(4-br0mophenoxy)-4,6-dibromophenyH-ester. 162-167 43- N-pheuyl-carbamic acid-O-12-(2,4-dichlorophenoxy)-5-ehlorophenyl]-ester 150-151 44.. N henyl-thiocarbamic acid -O-[2-(2 ,4'-diehlorophenoxy)-5-ch1oropheny1l-ester 105-107 45 N- l-fiuorophenyD-carbamic aeid-O-[2-(2,4-dich1orophenoxy)-5-chlorophenyl]-ester 144-146 46 N-(2-chloropheuyl)-carba1nic acid-O-[2-(2',4'-diehlorophenoxy)-5-chlnrophenyli-esten -107 47- N-( L-chlorophenyl)-carbamic acid-O-,2-(2,4-dichlorophenoxy) -5-ch1oropheny!]-ester 153-154 48- N-( l-chlorophenyl)-thiocarbamie acid-O-j-(2,4'-dichlorophenoxy)-5-ehl0r0phenyll-este 98-101 49. N-(2-bromophenyl) -earbamic acid-O-[Z-(2',4-diehlurophenoxy)-5-ehlorophenyl]-ester -111 50. N-(3-hromopheny1)-carbamie acid-O-,2-(2,4'-dicl1l0rophenoxy) -5-ch1or0phenyl]-ester 126-128 81 N-(4-brom0pheny1)-carbamic acid-0 242 ,4'-dichlorophenoxy)-5-chl0rophenyl]-ester 159-160 62.. N -(4-bromophenyl)-thiocarbamic acid-O-,2-(2',4-dichl0rophenoxy)-5-ehlorophenyl]-este 106-107 53 N-(3,4-dichlorophenyl)-carbamie acid-O 2-(2,4-dichlor0phenoxy) -5-chlorophenyl'-ester 145-147 54 N -(3,5-dieh1oropheny1)carbamic acid-0 242,4-dichlorophenoxy)-5-chlorophenyli-ester 132-134 55. N-(3,4-diehlorophenyD-thiocarbamie acid-O42-(2,4'-diehlorophenoxy)-5-chlorophenyl]-este 99-102 68.- N-(2,4,5-tn'ehlorophenyl)-thiocarba:mic acid-O-[2-(2',4-dichlorophenoxy)-5ch1or0phenyl]-este 80-82 57 N-(S-trifiuoromethyl--chlorophenyl)-carbamic acid-O-[2-(2,4-diehlorophenoxy)-5-chlorophenyl]- -12 (9) Blue stain: Scoplularia phyconiyes, Pullularia pullulans.

(C) Method.-The lowest growth-inhibiting concentration for the various microorganisms was determined by mixing the solution of active substance with nutrient agar while still warm. The agar is then poured into plates and,

In the following table are listed: the nutrient media used for the various organisms, the incubation temperature and incubation time, as well as the concentration of the active substances used.

after solidification, inoculated with the test germs.

l p.p.m.=Parts of active substance per 10 parts of agar.

In the following Table 2, the bacteriostatic action, and in Table 3, the fungistatic action of some of the compounds listed in Table 1 on some of the previously listed micro- 20 organisms are given.

TABLE 2 Staph- Staph- 11lococ Staphy- Strepto- Brewylococcus lococcus Sarcina caucus Carynebacterium Escheri- Salmocus aureus saproph. Bacillus Bacillus Sar- Zutea faecalis bact. ammon. chia coli nella Proaureus ATCC N OTC pumt'lus subtzlis cina OTC NCTC diphter- ATOO N CTC pulloru'm teua SG 511 6538 7292 Fey NCTC ureae 196 8619 cities 17 6871 8196 VSlZ 8p.

10 30 3 10 10 30 30 30 30 1 10 10 10 10 3 10 10 30 30 30 30 10 1 10 10 1 30 1O 10 1O 10 30 30 30 30 1 1O 10 1 30 30 10 10 10 30 30 30 10 1 30 10 1 10 8 10 10 10 30 30 10 10 1 10 10 3 1O 3 3 1O 10 30 10 10 10 1 10 10 1 3 3 3 10 3 3 1 1 10 10 1 3O 30 10 10 30 30 30 30 1 30 10 3 10 1O 10 10 10 30 3D 10 10 10 10 10 1 10 10 10 10 30 30 30 3O 10 1 10 10 10 10 10 10 10 10 30 30 10 10 10 10 10 3 3 10 1 10 10 30 10 10 3 10 10 30 3 3 3 1 1O 3 3 3 10 3 8 3O 30 3 3 3 1 3 10 30 3 10 3 10 30 30 1 1 3 1 3 3 3 3 10 1 10 10 10 3 3 3 1 3 10 30 10 10 3 10 10 30 1 3 1 3 3 10 10 10 10 10 1 10 10 1 3 1 3 3 10 10 10 10 10 1 10 10 1 10 3 3 3 10 30 10 10 10 1 10 10 3 10 10 3 10 3O 10 10 10 1 10 10 3 3 10 1 10 3 10 10 3 1 10 10 1 3 1 10 3 10 10 10 10 10 1 10 10 3 10 10 3 10 30 10 10 10 1 10 10 1 10 3 3 3 30 a 10 10 .10 1 10 10 1 3 1O 3 10 10 10 10 10 10 1 10 10 1 3 1 10 3 10 10 10 1 10 10 3 3 1O 1 10 1O 10 3 1 10 10 1 10 10 3 3 3 10 1 10 10 1 10 1 3 3 10 10 3 1 10 10 1 10 1 3 3 10 10 3 1 10 10 1 10 10 3 3 10 10 3 1 10 10 1 1 1 3 10 10 10 10 1 10 10 3 10 1 3 1D 10 10 10 10 3 10 10 1 3 10 3 1O 1O 10 10 10 10 1 10 10 1 3 1 3 3 10 10 10 10 1O 1 10 10 1 1 1 3 3 10 10 10 10 1O 1 10 10 1 3 1 3 10 10 10 10 10 10 1 10 10 10 10 10 1 10 10 10 10 10 1 10 10 3 1 10 3 3 10 10 10 10 3 1 10 10 1 3 10 3 10 10 10 10 10 10 1 10 1 3 1 3 3 10 10 r 7 1D 1 10 10 1 1 1 1 1 10 1 3 10 10 1 1 1 1 3 1 10 10 10 1 3 1 1 3 10 3 10 10 30 1 10 1 3 3 10 1 3 10 1 1 3 1 3 10 3 10 1 10 10 1 1 3 1 3 3 10 3 10 7 1 3 10 10 1 1 1 1 1 1 1 1 10 1 3 10 10 1 1 3 1 3 1 3 10 1 3 10 10 1 Table 1.

TABLE 3 Asper- Peni- Fuaarium v s Paeci- Pallaqillas cillium oxzl- Candida Derma- Rhizopua lomyces Fungi laria flaws italicu'm sporam albicans tophyten nigrica'ns varioii imperfecti pullulana 30 30 30 10 30 .30 10-30 30 30 10 30 10 10 30 10-30 100 30 30 30 10 10 10-30 30 30 10 30 10 10 100 10-30 30 30 30 30 10 30 80 30 30 30 30 30 10 10 30 30 80 30 30 30 10 30 100 10 30 10 10 10 10 10 30 10 10 10 10 30 10 30 30 10 30 10 10 10 10 10 30 10 30 10 10 30 10 10 30 10 30 10 10 30 10 10 30 10 30 10 3 30 10 10 10 10 80 10 10 30 10 10 10 10 10 30 10 30 10 10 30 10 30 30 10 30 10 30 10 1O 30 10 30 30 30 30 10 10 30 10 80 30 10 30 10 30 30 10 30 10 10 100 10 80 30 30 30 10 30 30 10-30 30 30 30 30 10 10 30 10 30 10 3 30 10 30 30 30 30 10 30 30 10 30 30 30 30 10 30 3O 30 30 30 30 30 10 30 30 30 30 30 30 10 10 30 10 30 10 30 30 10 10 30 10 30 30 30 30 10 10 30 10-30 30 30 30 30 10 10 30 10-30 30 30 30 30 10 30 30 10 30 10 10 30 10 30 30 30 30 10 30 30 10-30 30 30 30 30 10 10 30 10-30 30 30 30 30 10 30 30 10 30 10 10 10 30 10 10 30 10 10 30 10 10 30 10 30 30 10 30 10 10 80 10 30 10 10 3O 10 10 30 10 30 10 10 30 10 10 30 10 30 10 10 30 10 10 30 10 30 10 10 10 30 10 10 30 10 10 10 30 10 10 The bacteriostatic and fungistatic activity of the compounds according to the invention was further determined by the following comparative test using the method described under (C) above.

The following microorganisms were used.

Test 1:

(a) Bacteria: Escherichia coli, Bacillus pumilus,

Sarcina ureae, Staphylococcus aureus, Proteus vulgaris HXL.

(b) Fungi: Aspergillus niger, Fusarium oxysporum, Candida albicans, Saccharomyces cerevisiae (yeast), Torula utilis (yeast).

Test 2:

Bacteria: Escherichia coli,

Proteus v'ulgaris HXL.

Salmonella pullorum,

The nutrient media used for the various organisms, the incubation temperature and incubation time, as well as the concentrations of the active substances used are listed in the following tatble:

As comparative substances were used the following compounds:

1 Known from British Pat. No. 1,139,343.

Incubation Concentration Time of active Temp, I substance Organisms Nutrient medium degrees Hours Days in, p.p.m.

(a) Bacteria Nutrient-agar 37 4s 1 ggfiaa 2 Wort-agar (for yeasts). 28 5 100-30-10 1 p.p.m.=Part of active substance per 10 parts of agar.

In the following Table 4 are given the results of Test 1 and in Table 5 those of Test 2. The figures indicate those concentrations, at which no growth can be determinated.

tests are performed with Escherichia coli or Staphylococcus aureus SG 511. The agar plates (in Petri dishes) were then incubated for 24 hours at 37 C. The growth TABLE 4 Bacteria Fungi Staph- Escherivlococcas Bacillus chia Asper- Faaarium Saccharoaurms pumilus Sarci'na NC'IG Proteus aillm azy- Candida myces Torula Cpd. N 0. (Table 1) SG 511 fey ureae 8196 uulparic maer aporam albicans cerevisae utilis 3 10 1 10 100 10 so 100 100 1 a 3 1 10 100 30 30 100 100 1 a 10 1 10 100 30 so 30 so 3 1 a 10 30 30 10 so 30 30 a 1 a 3 30 30 so 30 30 30 1 a 10 1 10 100 30 30 100 30 1 1 3 1 10 30 10 30 30 30 1 a 10 1 10 30 10 so so 30 1 1 10 10 10 30 10 30 a0 30 100 100 1 000 30 1,00o 1,000 300 1,000 1,000 1,000 100 100 1 000 100 1,000 1,000 300 1,000 1, 000 1, 000 100 100 1,000 100 1,000 1,000 300 1,000 1,000 1, 000 300 100 1,000 100 1,00o 1,000 300 300 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000

TABLEE on the agar plates was then evaluated visually. The results are compiled in Table 7 wherein Escherichia P l Sal all h h l 1 mi represents growt undert e teXti e samp e 1 NCTC 19 v I H0 Compound NO (Tabel) 8 6 mm represents no growth under the textile sample 2 i 33 gg 1 represents traces of growth under the textile sample. 16:: 1 10 10 TABLE 7 i as 13 1--- 22 ig 13 Bacterium Staphylococcus Escherichia E- 300 300 300 c ggg 23g 38g aureuc SG 511 colt Control 300 300 300 Concentration P P m Gpd. No. (Table 1) 6. 2 25 6. 2 25 The disinfectant effect of the compounds according to the invention was determined by means of the following I I tests.

(A) Germ count in the rinse bath-The third rinse bath containing the active ubstance to be tested was inod: culated with Staphylococcus aureus SG 511 and Escheri- F i i i chia coli. One ml. of this bath was added to 20 ml. nn- G j: tritive agar prepared according to MacConkey [Difco 00mm} Manual, 9th ed. (1953), p. 131] when testing Escherichia coli and to 20 ml. nutritive agar to which 0.5% by weight of potassium tellurite had been added when testing Staphylococcus aureus SG 511. The resultant mixture was put into Petri dishes which were incubated for 24 hours at 37 C. The viable germ count per mil of rinse bath was determined by counting the number of colonies formed on the agar plates. The results are compiled in Table 6.

TABLE 6 Bacterium Staphylococcus aurcus SG 51! Escherichia coli Concentration in, ppm. 1

Cpd. No. (Table 1) 6. 2 25 6. 2 25 3 0 0 1 0 5-- 0 0 G O 10. 0 0 (l 0 46. 0 0 1 0 51- 0 0 6 0 53- 0 0 1 0 55- 0 D 0 E 5 10 0 I 10 5 10 l 10 l 10 4 10 3 10 i 10 10 i 10 l 10 Control 5 10 5 10 10 5 10 l 1 part active substance per 10' parts rinse bath.

(B) Rinse bath disinfection test.Raw, unfinished cotton fabric which had not been treated with optical brightening agents was rinsed in the bath described under (A). The cotton fabric was punched into disks of 2.5 cm. in diameter. These disks were placed each on one agar' plate prepared according to MacConkey, supra, thereby using nutritive agar and nutritive agar containing 0.5% by weight of potassium tellurite depending on whether the 1 1 part active substance per 10 parts rinse bath.

(C) Inhibition test.l0 ml. of Bacto-Agar (Difco No. B were each poured into Petri dishes. 10 ml. of molten agar prepared as stated under (A) above and inoculated with Staphylococcus aureus SG 511 and Escherichia coli were overlaid on each of the Petri dishes containing the Bacto-Agar. Cotton fabric disks treated according to (B) above were, after drying, each laid on a Petri dish, which was then incubated for 24 hours at 37 C. Thereafter, the zones wherein all growth of the bacteria had been inhibited were assessed in millimeters. The results obtained are given in Table 8, wherein signifies growth under the textile sample signifies no growth under the textile sample 1: signifies traces of growth under the textile sample TABLE 8 Bacterium Staphylococcus Escherichia aureus SG 511 coli Concentration in, p.p.m.

Cpd. No. (Table 1) 6. 2 25 6. 2 25 11- 6- 10- 15- 6- 10- 13- 9- 10- 11- 3- 4- 10- 4- 5- 11- 3- 5- 13- 5- 6- 0- (H- H- (H: 0+ 0+ 0+ 1 1 part active substance per 10 parts rinse bath.

The diphenyl-carbarnic acid esters of Formula I, produced according to the invention, have a broad and varied range of application for the control of microorganisms, especially of bacteria and fungi, and for the protection of organic materials and objects against attack by microorganisms. Thus, they can be directly worked into the material to be protected, for example into synthetic resin materials such as polyamides and polyvinyl chloride, into baths for the treatment of paper, into thickeners for printing inks, consisting of starch or cellulose derivatives, into lacquers and paints, containing casein for example, into cellulose, into viscose spinning masses, into paper, into animal mucilages or oils, into polyvinyl alcohol based permanent sizing agents, into cosmetic articles, into ointments or powders. In addition they can be added to preparation of inorganic or organic pigments for painters, plasticizers, etc. The new compounds are especially valuable for the protection of textiles of all kinds, e.g. textiles based on cellulose and keratin material, since they are notably substantive to such fiber materials.

In still other application forms, the carbamic acid esters of Formula I can be employed dissolved in organic solvents, for example as so-called sprays or as dry cleaners or to impregnate wood, the organic solvent being preferably non-miscible with Water, in particular petroleum fractions; but also water-miscible solvents such as lower alcohols, for example methanol or ethanol, or ethylene glycol monomethyl or monoethyl ether are suitable.

In addition, they can be employed together with wetting or dispersing agents in the form of aqueous dispersions, for example for the protection of substances which tend to rot such as for the protection of leather, paper, etc.

Solutions or dispersions of the active substances, which can be employed for the protection of these materials, preferably have a concentration of active substance of at least 0.005 g./liter.

A preferred field of application of the diphenyl carbamic acid esters of 'Formula I is the disinfection of washed goods and for the protection of washed goods against attack by microorganisms. For this purpose, rinse baths are used containing the said carbamic acid esters, advantageously in concentrations of about to 200 parts per million, calculated on the bath.

The bath can, in addition, also contain other usual auxiliaries such as optical brighteners, softeners, acidreacting salts such as ammonium or zinc silicofluoride or certain organic acids such as oxalic acid, also finishing agents, for example those based on synthetic resins or starch.

Suitable as wash goods which can be disinfected with rinse baths containing the compounds according to the invention are primarily organic fiber materials, namely that of natural origin such as cellulosic material, e.g. cotton; or polypeptide material, e.g. wool or silk; or synthetic fiber material such as that based on polyamide, polyacrylonitrile or polyester; or mixtures of the above fibers.

The carbamic acid esters according to the invention in the concentrations given, impart to the bath as Well as to the treated wash goods a broad and long-lasting disinfection against Staphylococcus and coli forms, which continues even after exposure of the active substance or the goods treated therewith to light. They are distinguished by their high stability to light on the goods treated therewith as well as by their high activity and broad range of action against gram-positive and gram-negative organisms.

The new carbamic acid esters are also very effective against the bacterial flora causing perspiration odor, and for that reason and because of their slight toxicity, they are suitable as deodorants for laundry or as additives for cosmetic agents such as ointment or creams.

Especially valuable is the use of the new carbamic acid esters of Formula I produced according to the invention as active substances for the healing of diseased conditions of the skin, the intestinal system and the urinal tract of warm-blooded animals, which is possible due to their excellent action against pathogenic bacteria and fungi, their 14 relatively low toxicity, as well as the fact that they are largely excreted from the body in an unchanged, active form.

The antimicrobial compositions according to the invention contain at least one diphenyl carbamic acid ester of Formula I as active ingredient, together with the usual pharmaceutical carriers. The type of carrier depends to a large extent on the intended use. Ointments, powders and tinctures are especially suitable for external application, for example for the disinfection of healthy skin as Well as for the disinfection of wounds and for the treatment of dermatoses and affections of the mucous membranes which are caused by bacteria or fungi. The ointment bases can be anhydrous, e.g. they can consist of mixtures of wool fat and Vaseline, or they can consist of aqueous emulsions in which the active substance is suspended. Suitable carriers for powders are, e.g. starches, such as rice starch, the bulk weight of which, if desired, can be made lighter, e.g. by the addition of highly dispersed silicic acid, or heavier by the addition of talcum. Tinctures contain at least one diphenyl carbamic acid ester of Formula I in aqueous ethanol, in particular 45-75% ethanol, to which, if desired, 10-20% glycerin may be added. Solutions prepared from the usual solubility promoters such as, e.g. polyethylene :glycol, as well as optionally, from emulsifying agents, are used in particular for the disinfection of healthy skin. The content of active ingredient in the above forms for external application is preferably between 0.1 and 5% Suitable for the disinfection of the mouth and throat are gargles, or concentrates for the prepartion thereof, in particular prepared from alcoholic solutions containing about 1-5 of active substance to which glycerin and/or flavorings can be added, and also lozenges, i.e. solid dosage units, having a relatively high content of sugar or similar substances and a relatively low content of active substance of about 02-20%, as well as the usual additives such as binding agents and flavorings.

For intestinal disinfection and for the oral treatment of infections of the urinal tract, in particular solid dosage unit forms such as tablets drages and capsules are suitable, which preferably contain between 10% and of a diphenyl carbamic acid ester of Formula I to enable the administration of daily doses of between 0.1 to 2.5 g. to adults or of suitably reduced doses to children.

Tablets and drage cores are produced by combining the carbamic acid esters of Formula I with solid, pulverulent carriers such as lactose, saccharose, sorbitol, maize starch, potato starch or amylopectin, cellulose derivatives or gelatin, preferably with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols of suitable molecular weight. Drage cores are then coated, for example, with concentrated sugar solutions which may also contain, e.g. gum arabic, talcum and/or titanium dioxide, or they are coated with a lacquer dissolved in volatile organic solvents or mixture of solvents. Dyestuifs can be added to these coatings, e.g. to difierentiate between varying dosages. Perles (pearlshaped, sealed gelatine capsules) and other closed capsules consist for example, of a mixture of gelatin and glycerin, and contain, e.g. mixtures of a new carbamic acid ester of Formula I with polyethylene glycol. Hard gelatine capsules contain, for example, granulates for an active substance with solid pulverluent carriers such as, e.g. lactose, saccharose, sorbitol, mannitol; starches such as potato starch, maize starch or amylopectin, celluose derivatives or gelatin, as well as magnesium stearate or stearic acid.

In all of the forms of administration, whether for technical, cosmetic, hygienic or medical use, the new diphenyl carbamic acid esters of Formula I can be present as sole active ingredient or they can be combined with other known antimicrobial, in particular antibacterial and/or antimycotic substances, for example to broaden the range of application. They can be combined, for example, with halogenated salicylic acid alkyl amides and anilides, with halogenated diphenyl ureas, with halogenated benzoxazoles or benzoxazolones, with polychlorohydroxy-diphenyl-methanes, with halogen-dihydroxy-diphenyl sulfides, with bactericidal 2-imino-imidazolidines or -tetrahydropyrimidines or with bactericidal quaternary compounds or with certain dithiocarbamic acid derivatives such as tetramethyl-thiuram disulfide. Optionally, carriers having themselves favora'ble pharmacological properties may also be used, such as sulfur as a powder base, or zinc stearate as a component of ointment bases.

In the following examples, a number of typical forms of application for various uses are described.

EXAMPLE 4 Wound dusting powder: 3.00 g. of active substance, 5.0 g. of zinc oxide and 41.9 g. of rice starch are thoroughly mixed with 50.0 g. of talcum which has been impregnated with 0.1 g. of perfume. The mixture is passed through a suitable, fine sieve and again well mixed.

EXAMPLE 5 Antiseptic ointment: 3.0 g. of active ingredient are triturated with 3.0 g. of paraflin oil, and added to a mixture of 10.0 g. of wool fat and 84.0 g. of white Vaseline, which has been melted at a moderate temperature. The mixture is allowed to cool while stirring.

EXAMPLE 6 Lozenges for the disinfection of the mouth and throat: 50.0 g. of active substance are carefully mixed with 400.0 g. of powdered sugar and the mixture is evenly moistened with a granulating solution of 8.0 g. of gelatine and 2.0 g. of glycerin in about 120 g. of water. The mass is granulated through a suitable sieve and dried. A sieved mixture of 3.0 g. of highly dispersed silicic acid, 4.0 g. of magnesium stearate, 0.7 g. of flavoring and 42.3 g. of talcum is added to the dry granulate and thoroughly mixed The mixture is pressed into 1000 tablets.

EXAMPLE 7 Gargle concentrate: 5.0 g. of active substance are dissolved in 60.0 g. of 96% ethanol, 15.0 g. of glycerin and 0.3 g. of flavoring are added and the solution is made up to 100.0 g. with 19.7 g. of distilled water. For gargling, about 5-20 drops of this concentrate are used in water.

EXAMPLE 8 Tablets for the disinfection of the intestines and the urinal tract: To prepare 1000 tablets each containing 150 mg. of active substance, first 150.0 g. of active substance are thoroughly mixed with 60.0 g. of maize starch and 35.0 g. of lactose, and the mixture is evenly moistened with a granulating solution prepared from 5.0 g. of gelatin and 3.0 g. of glycerin in about 70 g. of water. The mass is granulated through a suitable sieve and dried. The granulate is thoroughly mixed with a sieved mixture of 15.0 g. of talcum, 10.0 g. of dried maize starch and 2.0 g. of magnesium stearate. The mixture is pressed into 1000 tablets.

EXAMPLE 9 Drages for the disinfection of the intestines and the urinal tract: To prepare 1000 drage cores, first 150.0 g.

of active substance are thoroughly mixed with 60.0 g. of maize starch and 34.0 g. of lactose. This mixture is mixed with a binding agent consisting of 6.0 g. of starch, 3.0 g. of glycerin and about 54 g. of distilled water, and the mass obtained is granulated through a suitable sieve and dried. The granulate is thoroughly mixed with a sieved mixture of 15.0 g. of talcum, 10.0 g. of maize starch and 2.0 g. of magnesium stearate, and the mixture is pressed into 1000 drage cores each weighing 280 mg.

The above cores are coated in a coating pan with a layer consisting of: 2.000 g. of shellac, 7.500 g. of gum arabic, 0.180 g. of dyestuff, 2.000 g. of highly dispersed silicic acid, 35.00 g. of talcum and 58.320 g. of sugar. 1000 drages are obtained each weighing 385 mg. and containing mg. of active substance.

We claim:

1. An O,N-diphenylthiocarbamic acid ester of the formula wherein R represents phenoxy substituted by from 1 to 3 identical or different halogen atoms selected from the group consisting of fluorine, chlorine and bromine, one of R R and R represents chlorine or bromine, and each of the others of R R and R represents hydrogen, chlorine or bromine, each of R and R represents hydrogen, fluorine, chlorine, bromine, lower alkyl, lower alkoxy, halogenalower alkyl, nitro or hydroxy, and R represents hydrogen, fluorine, chlorine, bromine, lower alkyl, lower alkoxy, di-lower alkylamino or hydroxy. 2. N-(3-methylphenyl)-thiocarbamic acid-O-[2-(2',4'- dichlorophenoxy) -5-chlorophenyl] -ester.

3. N-(3 trifluoromethyl-4-chlorophenyl)-thiocarbamic acid-O- [2- (4'-chlorophenoxy -5-chlorophenyl] -ester.

4. N-(4-methylphenyl)-thiocarbamic acid-O-[2-(2,4'- dichlorophenoxy) -5-chlor0phenyl] -ester.

5. N-(3-methylphenyl)-thiocarbamic acid-O-[2-(2,4'- dichlorophenoxy) -5-chlor0phenyl] -ester.

I References Cited UNITED STATES PATENTS 3,609,177 9/1971 Traber et al. 260-455 A FOREIGN PATENTS 1,051,823 12/1966 Great Britain 260-455A LEWIS GO'ITS, Primary Examiner D. R. PHILLIPS, Assistant Examiner US. Cl. X.R. 

